So if you combine those two paradigms, you end up having a molecular basis that's likely to be a factor, a gene, that's a testis-determining factor, and that's the sex-determining gene. So the field based on that is really oriented towards findingtestis-determining factors. What we discovered, though, was not just pro-testis determining factors. There are a number of factors that are there, like WNT4, like DAX1, whose function is to counterbalance the male pathway.
Why are genes such as WNT4 and others necessary for sex development?
I don't know why it's necessary, but if they're doing this then probably they're here to do some fine-tuning at the molecular level. But these antimale genes may be responsible for the development of the ovary. And WNT4 is likely to be such a factor. It's an ovarian marker now, we know. But if you have an excess of WNT4, too much WNT4 in an XY, you're going to feminize the XY individual.
Is the conceptual framework for sex determination changing, then, because of these discoveries?
I think the frame has slightly changed in the sense that even though it's still considered that the ovary is the default pathway, it's not seen as the passive pathway. It's still "default" in the sense that if you don't have the Y chromosome, if you don't haveSRY, the ovary will develop. [SRY, or sex-determining region Y, encodes the so-called testis determining factor.] That's probably the new thing in the past 10 years, that there are genes that are essential to make a functioning ovary. That really has changed, and WNT4 is one of the reasons for it.
What do you feel are your group's most important contributions to the sex biology field so far?
The two things that we contributed was, one, to find the genes that are antimale, and reframing the view of the female pathway from passive to active. And the second thing is in the brain. We're the first ones to show that there were genes involved in brain sexual differentiation, making the brain either male or female, that were active completely independently from hormones. Those were probably our two main contributions.
Do you think this difference in gene expression in the brain explains anything about gender identity?
About identity, it says nothing [yet]. It might say something. So those genes are differentially expressed between males and females early during development. They're certainly good candidates to look at to be influencing gender identity, but they're just goodcandidates.
At a recent international meeting to discuss management of people with genital and gonadal abnormalities, you successfully pushed for a change in nomenclature. Instead of using terms such as "hermaphrodite" or even "intersex," you recommended that the field use specific diagnoses under the term, "disorders of sex development." Why did you and other geneticists feel a nomenclature change was necessary?
For the past 15 to 16 years now, there really has been an explosion in the genetic knowledge of sex determination. And the question being, how can we translate this genetic knowledge into clinical practice? So we said maybe we should have a fresh approach to this.
The initial agenda was to have a nomenclature that was robust but flexible enough to incorporate new genetic knowledge. Then we realized there were other problems that were in fact not really genetic, but that genetics could actually answer them. Ultimately individuals who are intersex will each have their diagnosis with a genetic name. It's not going to be some big, all-encompassing category, like "male hermaphrodites." And that's much more scientific, it's much more individualized, if you will. It's much more medical.
How did the conference participants respond to the proposal?
The majority of health care professionals were very happy with it. There were some, there was a conservative side that said, "Why change something that was working?" There was significant minority dissent that was saying, "Why do we care?" Because it was working, for us it's an intellectual frame that has worked. So it required a little bit of education, saying, you know, it's important not only because it's more precise and it's more scientific, but also the patients would benefit from it by removing the word "hermaphrodite" and so forth. About the change to disorders of sex development, there was no issue at all in the group.